Open access peer-reviewed chapter

Apoptotic Inhibitors as Therapeutic Targets for Cell Survival

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El-Shimaa Mohamed Naguib Abdelhafez, Sara Mohamed Naguib Abdelhafez Ali, Mohamed Ramadan Eisa Hassan and Adel Mohammed Abdel-Hakem

Submitted: December 16th, 2018 Reviewed: February 26th, 2019 Published: June 20th, 2019

DOI: 10.5772/intechopen.85465

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Apoptosis has revealed an essential function in the development or prevention of oncogenic transformation in the body; however, programmed cell death (PCD) must be tightly controlled since deregulated cell death is involved in the development of a large number of different pathologies. Apoptosis can be decreased in pathological states such as in cancer and autoimmunity or elevated such as in stroke, neurodegeneration, retinal cell death, myocardial and liver ischemia, inflammatory diseases such as sepsis, osteoarthritis (OA), rheumatoid arthritis (RA), and asthma. Different types of apoptotic inhibitors will be discussed in this chapter displaying their mechanism of action, which have been reported to be therapeutic targets for cell survival or at least limiting cell death. These inhibitors are classified according to their nature into natural antiapoptotic proteins that present mainly in the cell and synthetic small molecule inhibitors that are widely used to protect against overexpression of apoptosis mediators and, in turn, to prevent corresponding diseases.


  • antiapoptosis
  • mechanism
  • apoptotic inhibitors
  • endogenous
  • synthetic
  • cell survival

1. Introduction

Apoptosis is a crucial normal biological process that occurs in the cell as a component of animal development, tissue hemostasis, and immune response. In pathological state, it can be abrogated as in cancer and autoimmune diseases, or over-expressed as in case of stroke, ischemia, psoriasis, and inflammatory diseases.

The apoptotic mechanism occurs through either extrinsic pathway or intrinsic pathway, which leads to cell death through different apoptotic cascades, according to the type of stimuli [1].

These cell survival strategies involve a myriad of coordinated and systematic physiological and genetic changes that serve to ward off death [2].

There are various inhibitors of these pathways, which have been reported to be helpful in inhibition of the cell death or limiting it. These inhibitors are classified according to their nature into endogenous antiapoptotic proteins that present mainly in the cell to regulate the apoptosis process and synthetic inhibitors that are synthesized to be used in case of overexpression of apoptosis mediators as in some diseases.

1.1 Endogenous antiapoptotic inhibitors

1.1.1 Reduction in the number of apoptotic cells

It was reported that Ginkgo bilobaextract (EGb 761) exhibited antiapoptotic effect on different cell types [3], and it particularly inhibits death in human lymphocytes when exposed to gossypol, a toxin that causes cell death via apoptosis. Similar results have been observed in thymus cells pretreated with EGb 761 and then exposed to ferrous sulfate in hydrogen peroxide (H2O2) [4]. Lymphocytes that are isolated from spleen of aged mice and treated with EGb 761 were less susceptible to reactive oxygen species (ROS)-induced apoptosis [5]. Scientists revealed that the posttreatment with EGb 761 in the peripheral nervous system decreased efficiently the number of apoptotic cells in injured rat spinal cord [6]. Moreover, it helps in treatment of the central nervous system reduced neuronal death in the substantia nigra pars compactafrom an experimental model of Parkinson’s disease [7].

1.1.2 Maintaining the mitochondrial integrity

Rhodiola crenulata extract (RCE) is an edible alcohol extract, conserving greatly the mitochondrial integrity and in turn prohibiting the release of cytochrome C, which leads to cell death. The effective concentration of the most important component, salidroside, was ∼4% (w/w).

Other herbals mediate its antiapoptotic effect through the same mechanism as they possess a potent reactive oxygen species scavenging function; however, they restore the mitochondrial membrane potential [8, 9].

Some drugs were tested in sympathoadrenal cells that showed obviously another antiapoptotic pathway through inducing the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) transcription rate and B-cell lymphoma-extra-large (Bcl-xL) proteins. The role of these proteins appears crucial, because inhibition of their production by antisense oligonucleotides (directed toward the translation initiation site of the Bcl-2 transcript) resulted in aboliting protective effect. The prosurvival pathway also included activation of the transcription nuclear factors NF-κB (a protein complex that controls transcription of DNA, cytokine production, and cell survival) and CREB (cellular transcription factor). It binds to certain DNA sequences and the antiapoptotic kinase PKCα/β such as dehydroepiandrosterone (DHEAS) and Allo [10].

1.1.3 Decrease in caspase transcription rate and DNA fragmentation

Some natural component reverse such as diosmin induces Bad and Bax, pro-apoptotic members of the Bcl-2 family, to react with the mitochondrial membrane and prevent the release of apoptotic-inducing factor (AIF) and cytochrome-C. Cytochrome-C in turn inhibits initiator caspase-9, which prevents sequential cascade of activation of caspase-3, and conserves DNA fragment along with no apoptotic cell death [11].

1.2 Synthetic apoptotic inhibitors

1.2.1 Tumor necrotic factor (TNF) inhibitors

Infliximab (IFX) [12], etanercept (ETN) [13], Adalimumab (ADA), golimumab (GOLI) [14], and certolizumab pegol (CZP) [15] are clinical biologic drugs that act as necrotic factor (TNF)-α inhibitors that were approved by the U.S. Food and Drug Administration (FDA). Other synthetic TNF inhibitors were designed such as:

Compound (1) inhibited the release of TNF in cells and in animals. It was active in a chronic rheumatoid arthritis model (MCIA) when administrated orally and it was advanced for further preclinical evaluation [16]. A novel thalidomide analog was synthesized and characterized for anti-TNF-α activity with up to a 38% inhibition for compound (2) with no obvious concentration dependence [17].

Compound (3) is an oleanolic acid analog, characterized by structural modifications at position C-3 and C-28 of oleanane skeleton and tested for anti-inflammatory potential, when C-3 became Indole, and C-28 = cyclohexamine, gave mild inhibition by 51.9% [18]. Compound (4) suppressed serum TNF-α levels by 2.45 ng/ml compared to the control group 5.61 ng/ml [19].

Compound (5) possessed TNF inhibition with half-maximal inhibitory concentration (IC50) = 0.5 μm [19]. Besides, Compound (6) decreased the level of the pro-inflammatory cytokine TNF-α by (39.19%) [20].

Compound (7) had 56% inhibition of TNF-α at 10 μm [21]. Betulinic acid (8) had a significant decrease in IL1β, IL6, and TNFα in the neuronal tissues [22].

1.2.2 Fatty acid synthase (Fas) inhibitors

KR-33493 (9) was used as a potent inhibitor for ischemia Fas-mediated cell death 68 [23]. Compound (10a, b) RKTS-33,34 with 10 μm ED50 value (concentration causing 50% of maximum effect) selectively inhibited apoptosis induced by FasL as well as ECH (epoxycyclohexenone derivative) (11), which is produced by fungus [24].

Glycine (12) was tested as a cytoprotector against ischemic damage by downregulation of FasL/Fas and caspase3 and upregulation of Bcl2 and Bcl2-bax (apoptosis regulator BAX) [25]. Compound (13) was designed as a novel class of ischemic cell death inhibitors targeting Fas-mediated cell death pathway with EC50 = 0.557 μm (the concentration of a drug that gives half-maximal response), and cell survival = 92.98% at 10 μm [26]. It was found that (dichlorovinyl dimethyl phosphate) DDVP (14) significantly decreased the expression of Fas antigen on YAC-1S target cells and the expression of FasL (Fas ligand) on LAK cells (lymphokine-activated killer cell). These findings provided direct evidences that DDVP impaired the FasL/Fas pathway via downregulating the expression of both Fas and FasL [27]. Geldanamycin (15), which was originally discovered in Streptomyces hygroscopicus [28], inhibited Fas signaling pathway and protected neurons against ischemia [29].

Compound (16) is the active form of vitamin D that inhibited Fas ligand-induced apoptosis in human osteoblasts by regulating components of both the mitochondrial and Fas-related pathways [30]. Estrogen (17) also inhibited Fas-mediated apoptosis in experimental stroke [31].

Cilazapril (18) acts as an angiotensin-converting enzyme inhibitor along with protection against apoptosis through downregulating Fas protein during the induction of apoptosis in cardiomyocytes in rat hearts when subjected to reperfusion after ischemia [32]. M50054 (19) (cell-permeable inhibitor of the activation of caspase-3) inhibited apoptosis induced by a variety of apoptotic stimuli such as the Fas/Fas ligand system and etoposide. Thus, it might be effective for hepatitis when administered orally and chemotherapy-induced alopecia when administered topically [33].

SC79 (20) (AKT activator) prevented acute hepatic failure induced by Fas-mediated apoptosis of hepatocytes [34]. Vit K2 (21) significantly suppressed both Fas expression and Fas-mediated apoptosis of the cells in a dose-dependent fashion. The maximum effect was observed when 6–10 mol/L of vitamin K2 was added to the culture, a concentration comparable to that attained during therapy with vitamin K2 [35].

Vanillic acid (22) inhibited Fas-receptor and caspase-mediated apoptosis signaling pathway and so acted as cardioprotective [36]. NCX-1000 (NO-releasing derivative of ursodeoxycholic acid) (23) is a nitric oxide (NO) derivative of ursodeoxycholic acid (UDCA). When an NO-releasing moiety is added to UDCA, the effectiveness in preventing Fas-mediated liver injury increased [37].

1.2.3 BH3 interacting-domain death agonist (BID) inhibitors

BID plays a central role in the apoptotic machinery mediating cytochrome C and SMAC/DIABLO (mitochondrial protein that potentiates some forms of apoptosis) released from mitochondria, a crucial event for caspase activation and cell death [38]. Pharmacological inhibition of BID could therefore provide a protective benefit against pathological cell death, occurring in cerebral ischemia [39], neurodegenerative diseases [40, 41], liver inflammation [42], or other illnesses where BID has been implicated [43].

BI-6C9 (24) was effective in inhibiting the carboxyl-terminal fragment (tBid) (truncated protein) association with isolated mitochondria at 20 μm [39]. TC9-305 (2-sulfonyl-pyrimidinyl derivatives) (25) had an EC50 = 0.23 nm [44]. BI-11A7 (26) was much more effective in this assay when compared with BI-6C9 (24) but showed some toxicity at higher concentrations (20 μm) [45]. 3-o-tolylthiazolidine-2,4-dione (27) protected neural cells against glutamate- and tBid-induced toxicity with an EC50 = 6.78 μm [46].

1.2.4 Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) inhibitors

TWEAK also known as (Apo3L or TNFSF12) was first described as an inducer of apoptosis in transformed cell lines [47]. It is a member of the tumor necrosis factor (TNF) receptor family that is induced in a variety of cell types in situations of tissue injury. It is a crucial player in muscle atrophy, cerebral ischemia, kidney injury, atherosclerosis, and infarction, as well as in various autoimmune scenarios including experimental autoimmune encephalitis, rheumatoid arthritis, and inflammatory bowel disease [48]. Aurintricarboxylic acid (ATA) (28) was a potent inhibitor of the TWEAK-Fn14 signaling axis and could potentially be utilized to enhance the therapeutic response in glioblastoma (GBM) [49]. L524-0366 (29) was a specific dose-dependent inhibitor of TWEAK-Fn14 interaction [50] and it was found to be a complete suppressor for TWEAK-induced T98G cell migration at dose equal to 10 μm [51].

1.2.5 Cytochrome C inhibitors

Cytochrome C is the specific and efficient electron transfer mediator between the two last redox complexes of the mitochondrial respiratory chain [52]. The release of cytochrome C from the mitochondria into the cytoplasm results in caspase-9 activation leading to cell death [43]. Minocycline (30) directly inhibited the release of cytochrome C from mitochondria. Therefore, it was beneficial in experimental models of stroke, traumatic brain and spinal cord injury, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and multiple sclerosis [53, 54]. Methazolamide (31) was FDA approved for the treatment of glaucoma, while melatonin (32) inhibited oxygen/glucose deprivation—induced cell death, loss of mitochondrial membrane potential, release of mitochondrial factors, pro-IL-1β processing, and activation of caspase-1 and -3 in primary cerebrocortical neurons. Furthermore, compounds (32, 33) decreased infarct size and improved neurological scores after middle cerebral artery occlusion in mice [54, 55, 56]. Gamma-tocotrienol (GTT) (33) had the antiapoptotic effects by preventing the activation of caspase-3 and caspase-9, reducing the release of cytochrome C from the mitochondria and preventing H2O2-induced apoptosis in human diploid fibroblasts (HDFs), and delayed cellular aging [57].

3-hydroxypropyl-triphenylphosphonium (TPP)-conjugated imidazole-substituted oleic acid (TPP-IOA(34a)) and stearic acid (TPP-ISA(34b)) exerted strong specific liganding of heme-iron in cytochrome C/cardiolipin (CL) complex and effectively suppressed its peroxidase activity and CL peroxidation, thus preventing cytochrome C release and cell death, and protecting mice against lethal doses of irradiation [58, 59]. TPP-6-ISA (35) was an effective inhibitor of the peroxidase function of cyt c/CL complexes with a significant antiapoptotic activity that realized in mouse embryonic cells exposed to ionizing irradiation [60, 61].

1.2.6 P53 upregulated modulator of apoptosis (PUMA) inhibitors

It is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli 106. PUMA inhibitors may provide radiation protection and mitigation, there were three compounds that had a strong PUMA inhibition and that were designed by Gabriela Mustata et al., and data were not published due to intellectual property protection [62].

CLZ-8 (36) was capable of targeting a PUMA protein and has very good physicochemical properties, very good apoptosis resistance, and radiation protection effects. It was found to protect cells from DNA damage under the concentration of 1 μm [63].

1.2.7 Bax inhibitors

Xanthan gum (XG) (37) is an extracellular polysaccharide secreted by microorganisms and was first discovered during fermentation process using Xanthomonas campestris. It could protect subchondral trabecular in bone subchondral, decrease the apoptosis of chondrocytes, downregulate the expressions of active caspase-9, active caspase-3 and bax, and upregulate the expression of bcl-2. Lower range of molecular weight of xanthan gum (LRWXG) could upregulate the expression of cytochrome C in mitochondria while downregulating the expression of cytochrome C in cytoplasm. These findings showed that LRWXG could inhibit cartilage degradation via an intrinsic bax-mitochondria cytochrome C-caspase pathway [64].

PD98059 (38) showed inhibition of staurosporine-, UV-, anticancer drug-induced apoptosis in vitro and protected brain against cell death through inhibition of BAX and other factors [65, 66]. Vitamin E (39) significantly reduced the effects of gentamicin on BAX and BCL-2 expression levels [67].

Tanshinone (40) could inhibit the expression of Bax and stimulated the expression of Bcl-2 in cardiomyocytes in the ischemia-reperfusion rat model [68].


2. Conclusion

Apoptotic inhibitors regulate cell proliferation by promoting cell survival. One promising area of research that has been covered extensively in this review is displaying the recent developed apoptotic inhibitors and their significance to functional therapies for a number of diseases and pathophysiologies. These inhibitors are working through numerous built-in avenues’ mechanisms, including inhibition of pro-apoptotic and apoptotic factors. Our perspectives are to develop new therapeutic strategies aiming to participate in treatment of serious diseases such as stroke, neurodegeneration, retinal cell death, myocardial and liver ischemia, sepsis, osteoarthritis (OA), rheumatoid arthritis (RA), and asthma or to reduce the adverse effects accompanied with long-term therapy of cancer and autoimmunity. Hopefully, scientists will soon be able to provide every patient suffering from imbalanced apoptotic disease with a more specified and suitable therapy.


Conflict of interest

No financial or commercial conflicts of interest were declared by all authors.


  1. 1. Guicciardi ME, Gores GJ. Apoptosis: A mechanism of acute and chronic liver injury. Gut. 2005;54(7):1024-1033
  2. 2. Portt L, Norman G, Clapp C, Greenwood M, Greenwood MT. Anti-apoptosis and cell survival: A review. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2011;1813:238-259
  3. 3. Ergun U, Yurtcu E, Ergun MA. Protective effect ofGinkgo bilobaagainst gossypol-induced apoptosis in human lymphocytes. Cell Biology International. 2005;29:717-720
  4. 4. Tian Y-M, Tian H-J, Zhang G-Y, Dai Y-R. Effects ofGinkgo bilobaextract (EGb 761) on hydroxyl radical-induced thymocyte apoptosis and on age-related thymic atrophy and peripheral immune dysfunctions in mice. Mechanisms of Ageing and Development. 2003;124:977-983
  5. 5. Schindowski K, Leutner S, Kressmann S, Eckert A, Müller WE. Age-related increase of oxidative stress-induced apoptosis in mice prevention byGinkgo bilobaextract (EGb761). Journal of Neural Transmission. 2001;108:969-978
  6. 6. Ao Q, Sun X, Wang A, Fu P, Gong K, Zuo H, et al. Protective effects of extract ofGinkgo biloba(EGb 761) on nerve cells after spinal cord injury in rats. Spinal Cord. 2006;44:662
  7. 7. Rojas P, Serrano-García N, Mares-Sámano JJ, Medina-Campos ON, Pedraza-Chaverri J, Ögren SO. EGb761 protects against nigrostriatal dopaminergic neurotoxicity in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced Parkinsonism in mice: Role of oxidative stress. European Journal of Neuroscience. 2008;28:41-50
  8. 8. Singh BK, Tripathi M, Chaudhari BP, Pandey PK, Kakkar P. Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. PLoS ONE. 2012;7:e34200
  9. 9. Wang J-m, Qu Z-q, Wu J-l, Chung P, Zeng Y-S. Mitochondrial protective and anti-apoptotic effects ofRhodiola crenulataextract on hippocampal neurons in a rat model of Alzheimer's disease. Neural Regeneration Research. 2017;12:2025
  10. 10. Charalampopoulos I, Tsatsanis C, Dermitzaki E, Alexaki V-I, Castanas E, Margioris AN, et al. Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins. Proceedings of the National Academy of Sciences. 2004;101:8209-8214
  11. 11. Dholakiya SL, Benzeroual KE. Protective effect of diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF-α expression. Toxicology in Vitro. 2011;25:1039-1044
  12. 12. Danese S. Mechanisms of action of infliximab in inflammatory bowel disease: An anti-inflammatory multitasker. Digestive and Liver Disease. 2008;40:S225-S228
  13. 13. Couderc M, Mathieu S, Tournadre A, Dubost J-J, Soubrier M. Acute ocular myositis occurring under etanercept for rheumatoid arthritis. Joint, Bone, Spine. 2014;81(5):445-446
  14. 14. Renna S, Mocciaro F, Ventimiglia M, Orlando R, Macaluso FS, Cappello M, et al. A real life comparison of the effectiveness of adalimumab and golimumab in moderate-to-severe ulcerative colitis, supported by propensity score analysis. Digestive and Liver Disease. [Epub ahead of print]. 2018;50:1292-1298
  15. 15. Motlis A, Boktor M, Jordan P, Cvek U, Trutschl M, Alexander JS. Two year follow-up of Crohn’s patients substituted to certolizumab anti-TNFa therapy: SAVANT 2. Pathophysiology. 2017;24(4):291-295
  16. 16. Chen JJ, Dewdney N, Lin X, Martin RL, Walker KA, Huang J, et al. Design and synthesis of orally active inhibitors of TNF synthesis as anti-rheumatoid arthritis drugs. Bioorganic & Medicinal Chemistry Letters. 2003;13(22):3951-3954
  17. 17. Tweedie D, Luo W, Short RG, Brossi A, Holloway HW, Li Y, et al. A cellular model of inflammation for identifying TNF-α synthesis inhibitors. Journal of Neuroscience Methods. 2009;183(2):182-187
  18. 18. Bhandari P, Patel NK, Gangwal RP, Sangamwar AT, Bhutani KK. Oleanolic acid analogs as NO, TNF-α and IL-1β inhibitors: Synthesis, biological evaluation and docking studies. Bioorganic & Medicinal Chemistry Letters. 2014;24(17):4114-4119
  19. 19. Khalil NA, Ahmed EM, Mohamed KO, Zaitone SA-B. Synthesis of new nicotinic acid derivatives and their evaluation as analgesic and anti-inflammatory agents. Chemical & Pharmaceutical Bulletin. 2013;61(9):933-940
  20. 20. Kumar RS, Antonisamy P, Almansour AI, Arumugam N, Periyasami G, Altaf M, et al. Functionalized spirooxindole-indolizine hybrids: Stereoselective green synthesis and evaluation of anti-inflammatory effect involving TNF-α and nitrite inhibition. European Journal of Medicinal Chemistry. 2018;15:2417-2423
  21. 21. Dhuru S, Bhedi D, Gophane D, Hirbhagat K, Nadar V, More D, et al. Novel diarylheptanoids as inhibitors of TNF-α production. Bioorganic & Medicinal Chemistry Letters. 2011;21(12):3784-3787
  22. 22. Wang D, Chen P, Chen L, Zeng F, Zang R, Liu H, et al. Betulinic acid protects the neuronal damage in new born rats from isoflurane-induced apoptosis in the developing brain by blocking FASL-FAS signaling pathway. Biomedicine & Pharmacotherapy. 2017;95:1631-1635
  23. 23. Yoo S, Yu C, Jung S, Kim E, Kang NS. Design and synthesis of fluorescent and biotin tagged probes for the study of molecular actions of FAF1 inhibitor. Bioorganic & Medicinal Chemistry Letters. 2016;26(4):1169-1172
  24. 24. Kakeya H, Miyake Y, Shoji M, Kishida S, Hayashi Y, Kataoka T, et al. Novel non-peptide inhibitors targeting death receptor-mediated apoptosis. Bioorganic & Medicinal Chemistry Letters. 2003;13(21):3743-3746
  25. 25. Lu Y, Zhang J, Ma B, Li K, Li X, Bai H, et al. Glycine attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal apoptosis in mice. Neurochemistry International. 2012;61(5):649-658
  26. 26. Suh J, Yi KY, Lee Y-S, Kim E, Yum EK, Yoo S. Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors. Bioorganic & Medicinal Chemistry Letters. 2010;20(22):6362-6365
  27. 27. Li Q, Nakadai A, Takeda K, Kawada T. Dimethyl 2,2-dichlorovinyl phosphate (DDVP) markedly inhibits activities of natural killer cells, cytotoxic T lymphocytes and lymphokine-activated killer cells via the Fas-ligand/Fas pathway in perforin-knockout (PKO) mice. Toxicology. 2004;204(1):41-50
  28. 28. He W, Wu L, Gao Q, Du Y, Wang Y. Identification of AHBA biosynthetic genes related to geldanamycin biosynthesis inStreptomyces hygroscopicus17997. Current Microbiology. 2006;52(3):197-203
  29. 29. Yin X-H, Han Y-L, Zhuang Y, Yan J-Z, Li C. Geldanamycin inhibits Fas signaling pathway and protects neurons against ischemia. Neuroscience Research. 2017;12:433-439
  30. 30. Duque G, El Abdaimi K, Henderson JE, Lomri A, Kremer R. Vitamin D inhibits Fas ligand-induced apoptosis in human osteoblasts by regulating components of both the mitochondrial and Fas-related pathways. Bone. 2004;35(1):57-64
  31. 31. Jia J, Guan D, Zhu W, Alkayed NJ, Wang MM, Hua Z, et al. Estrogen inhibits Fas-mediated apoptosis in experimental stroke. Experimental Neurology. 2009;215(1):48-52
  32. 32. Xie Z, Koyama T, Abe K. Effects of an angiotensin-converting enzyme inhibitor on the expression of Fas protein and on apoptosis in rat ventricles subjected to reperfusion after ischemia. Current Therapeutic Research. 2000;61(6):358-366
  33. 33. Tsuda T, Ohmori Y, Muramatsu H, Hosaka Y, Takiguchi K, Saitoh F, et al. Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia. European Journal of Pharmacology. 2001;433(1):37-45
  34. 34. Liu W, Jing Z-T, Wu S-X, He Y, Lin Y-T, Chen W-N, et al. Novel AKT activator, SC79, prevents acute hepatic failure induced by Fas-mediated apoptosis of hepatocytes. The American Journal of Pathology. 2018;188(5):1171-1182
  35. 35. Urayama S, Kawakami A, Nakashima T, Tsuboi M, Yamasaki S, Hida A, et al. Effect of vitamin K2 on osteoblast apoptosis: Vitamin K2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. Journal of Laboratory and Clinical Medicine. 2000;136(3):181-193
  36. 36. Stanely Mainzen Prince P, Dhanasekar K, Rajakumar S. Vanillic acid prevents altered ion pumps, ions, inhibits Fas-receptor and caspase mediated apoptosis-signaling pathway and cardiomyocyte death in myocardial infarcted rats. Chemico-Biological Interactions. 2015;23:268-276
  37. 37. Fiorucci S, Mencarelli A, Palazzetti B, Del Soldato P, Morelli A, Ignarro LJ. An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(5):2652-2657
  38. 38. Adrain C, Creagh EM, Martin SJ. Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. The EMBO Journal. 2001;20(23):6627-6636
  39. 39. Becattini B, Sareth S, Zhai D, Crowell KJ, Leone M, Reed JC, et al. Targeting apoptosis via chemical design: Inhibition of bid-induced cell death by small organic molecules. Chemistry & Biology. 2004;11(8):1107-1117
  40. 40. Yuan J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis. 2009;14(4):469-477
  41. 41. Martin NA, Bonner H, Elkjær ML, D’Orsi B, Chen G, König HG, et al. BID mediates oxygen-glucose deprivation-induced neuronal injury in organotypic hippocampal slice cultures and modulates tissue inflammation in a transient focal cerebral ischemia model without changing lesion volume. Frontiers in Cellular Neuroscience; Feb 3 2016;10:14. DOI: 10.3389/fncel.2016.00014
  42. 42. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. Journal of Hepatology. 2013;59(3):583-594
  43. 43. Wang C, Youle RJ. The role of mitochondria in apoptosis. Annual Review of Genetics. 2009;43:95-118
  44. 44. Li L, Jiang X, Huang S, Ying Z, Zhang Z, Pan C, et al. Discovery of highly potent 2-sulfonyl-pyrimidinyl derivatives for apoptosis inhibition and ischemia treatment. ACS Medicinal Chemistry Letters. 2017;8(4):407-412
  45. 45. Becattini B, Culmsee C, Leone M, Zhai D, Zhang X, Crowell KJ, et al. Structure–activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting bid. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(33):12602-12606
  46. 46. Oppermann S, Schrader FC, Elsässer K, Dolga AM, Kraus AL, Doti N, et al. Novel N-phenyl–substituted thiazolidinediones protect neural cells against glutamate- and tBid-induced toxicity. The Journal of Pharmacology and Experimental Therapeutics. 2014;350(2):273-289
  47. 47. Maecker H, Varfolomeev E, Kischkel F, Lawrence D, LeBlanc H, Lee W, et al. TWEAK attenuates the transition from innate to adaptive immunity. Cell. 2005;123(5):931-944
  48. 48. Wajant H. The TWEAK-Fn14 system as a potential drug target. British Journal of Pharmacology. 2013;170(4):748-764
  49. 49. Roos A, Dhruv HD, Mathews IT, Inge LJ, Tuncali S, Hartman LK, et al. Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells. Oncotarget. 2017;8(7):12234-12246
  50. 50. Tran N, Meurice N, Dhruv H. FN14 antagonists and therapeutic uses thereof. 2016. US9238034B2
  51. 51. Dhruv H, Loftus JC, Narang P, Petit JL, Fameree M, Burton J, et al. Structural basis and targeting of the interaction between fibroblast growth factor-inducible 14 and tumor necrosis factor-like weak inducer of apoptosis. The Journal of Biological Chemistry. 2013;288(45):32261-32276
  52. 52. Maneg O, Malatesta F, Ludwig B, Drosou V. Interaction of cytochrome C with cytochrome oxidase: Two different docking scenarios. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2004;1655:274-281
  53. 53. Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, Ona V, Li M, et al. Minocycline inhibits cytochrome C release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417(6884):74-78
  54. 54. Wang X, Zhu S, Pei Z, Drozda M, Stavrovskaya IG, Del Signore SJ, et al. Inhibitors of cytochrome C release with therapeutic potential for Huntington’s disease. The Journal of Neuroscience. 2008;28(38):9473-9485
  55. 55. Wang X, Figueroa BE, Stavrovskaya IG, Zhang Y, Sirianni AC, Zhu S, et al. Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke. [Epub ahead of print]. 2009;14:1877-1885
  56. 56. Li M, Wang W, Mai H, Zhang X, Wang J, Gao Y, et al. Methazolamide improves neurological behavior by inhibition of neuron apoptosis in subarachnoid hemorrhage mice. Scientific Reports. 2016;6:35055
  57. 57. Makpol S, Abdul Rahim N, Kien Hui C, Ngah W, Zurinah W. Inhibition of mitochondrial cytochrome C release and suppression of caspases by gamma-tocotrienol prevent apoptosis and delay aging in stress-induced premature senescence of skin fibroblasts. Oxidative Medicine and Cellular Longevity. 2012;2012:1-13. Available from:[Accessed: September 24, 2018]
  58. 58. Atkinson J, Kapralov AA, Yanamala N, Tyurina YY, Amoscato AA, Pearce L, et al. A mitochondria-targeted inhibitor of cytochrome C peroxidase mitigates radiation-induced death. Nature Communications. 2011;2:497
  59. 59. Bakan A, Kapralov AA, Bayir H, Hu F, Kagan VE, Bahar I. Inhibition of peroxidase activity of cytochrome C: De novo compound discovery and validation. Molecular Pharmacology. 2015;88(3):421-427
  60. 60. Jiang J, Bakan A, Kapralov AA, Silva KI, Huang Z, Amoscato AA, et al. Designing inhibitors of cytochrome C/cardiolipin peroxidase complexes: Mitochondria-targeted imidazole-substituted fatty acids. Free Radical Biology & Medicine. 2014;71:221-230
  61. 61. Ghosh AP, Walls KC, Klocke BJ, Toms R, Strasser A, Roth KA. The pro-apoptotic BH3-only, Bcl-2 family member Puma is critical for acute ethanol-induced neuronal apoptosis. Journal of Neuropathology and Experimental Neurology. 2009;68(7):747-756
  62. 62. Mustata G, Li M, Zevola N, Bakan A, Zhang L, Epperly M, et al. Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death. Current Topics in Medicinal Chemistry. 2011;11(3):281-290
  63. 63. Feng T, Liu J, Zhou N, Wang L, Liu X, Zhang S, et al. CLZ-8, a potent small-molecular compound, protects radiation-induced damages both in vitro and in vivo. Environmental Toxicology and Pharmacology. 2018;61:44-51
  64. 64. Shao X, Chen Q, Dou X, Chen L, Wu J, Zhang W, et al. Lower range of molecular weight of xanthan gum inhibits cartilage matrix destruction via intrinsic bax-mitochondria cytochrome C-caspase pathway. Carbohydrate Polymers. 2018;198:354-363
  65. 65. Sawatzky DA, Willoughby DA, Colville-Nash PR, Rossi AG. The involvement of the apoptosis-modulating proteins ERK 1/2, Bcl-xL and Bax in the resolution of acute inflammation in vivo. The American Journal of Pathology. 2006;168(1):33-41
  66. 66. Nguyen Thi PA, Chen M-H, Li N, Zhuo X-J, Xie L. PD98059 protects brain against cells death resulting from ROS/ERK activation in a cardiac arrest rat model. Oxidative Medicine and Cellular Longevity. 2016;2016:3723762. Available from:[Accessed: December 10, 2018]
  67. 67. Kandeil MAM, Hassanin KMA, Mohammed ET, Safwat GM, Mohamed DS. Wheat germ and vitamin E decrease BAX/BCL-2 ratio in rat kidney treated with gentamicin. Beni-Suef University Journal of Basic and Applied Sciences. 2018;7(3):257-262
  68. 68. Guo R, Li G. Tanshinone modulates the expression of Bcl-2 and Bax in cardiomyocytes and has a protective effect in a rat model of myocardial ischemia-reperfusion. Hellenic Journal of Cardiology. [Epub ahead of print]. 2018;59:323-328

Written By

El-Shimaa Mohamed Naguib Abdelhafez, Sara Mohamed Naguib Abdelhafez Ali, Mohamed Ramadan Eisa Hassan and Adel Mohammed Abdel-Hakem

Submitted: December 16th, 2018 Reviewed: February 26th, 2019 Published: June 20th, 2019